Design and Synthesis of Imidazole and Triazole Pyrazoles as Mycobacterium Tuberculosis CYP121A1 Inhibitors.

Safaa M Kishk,Colin W Levy,Andrew W Munro,Samia M Mostafa,Mohamed A Helal,Sakshi Sood,Kirsty J Mclean,Luiz Pedro S De Carvalho,Claire Simons,Mohamed S Gomaa,Jack W.D Evans,Darren Smith,Ismail Salama

doi:10.1002/open.201900227

Abstract

The emergence of untreatable drug‐resistant strains of Mycobacterium tuberculosis is a major public health problem worldwide, and the identification of new efficient treatments is urgently needed. Mycobacterium tuberculosis cytochrome P450 CYP121A1 is a promising drug target for the treatment of tuberculosis owing to its essential role in mycobacterial growth. Using a rational approach, which includes molecular modelling studies, three series of azole pyrazole derivatives were designed through two synthetic pathways. The synthesized compounds were biologically evaluated for their inhibitory activity towards M. tuberculosis and their protein binding affinity (K D). Series 3 biarylpyrazole imidazole derivatives were the most effective with the isobutyl (10 f) and tert‐butyl (10 g) compounds displaying optimal activity (MIC 1.562 μg/mL, K D 0.22 μM (10 f) and 4.81 μM (10 g)). The spectroscopic data showed that all the synthesised compounds produced a type II red shift of the heme Soret band indicating either direct binding to heme iron or (where less extensive Soret shifts are observed) putative indirect binding via an interstitial water molecule. Evaluation of biological and physicochemical properties identified the following as requirements for activity: LogP >4, H‐bond acceptors/H‐bond donors 4/0, number of rotatable bonds 5–6, molecular volume >340 Å3, topological polar surface area <40 Å2.

Highlights

Introduction of aN atom in one of the phenyl rings, i. e. a pyridine ring, can potentially result in additional binding interactions, which may improve binding affinity
The requirement for two phenyl rings was explored in Series 2 by preparation of a small series of imidazole/triazole derivatives, with one of the phenyl rings replaced with a methyl group www.chemistryopen.org
In Series one of the phenyl rings is further substituted with a range of alkyl substituted phenyl and biaryl groups to determine structure-activity relationships (Figure 3)

Summary

Introduction

Introduction of aN atom in one of the phenyl rings, i. e. a pyridine ring, can potentially result in additional binding interactions, which may improve binding affinity. N atom in one of the phenyl rings, i. E. a pyridine ring, can potentially result in additional binding interactions, which may improve binding affinity. Extension of the chain between the pyrazole and the heme prosthetic group may allow the molecule to interact directly with the heme: this is the basis for Series 1 (Figure 3). The requirement for two phenyl rings was explored in Series 2 by preparation of a small series of imidazole/triazole derivatives, with one of the phenyl rings replaced with a methyl group www.chemistryopen.org (Figure 3). Our previous research showed a direct correlation between lipophilicity and MIC.[13] in Series one of the phenyl rings is further substituted with a range of alkyl substituted phenyl and biaryl groups to determine structure-activity relationships (Figure 3)

Methods

Results

Conclusion